WO1997016727A1 - Reduction de l'activite de fond pour un dosage, a l'aide de glycoproteines comportant des glucides oxydes - Google Patents

Reduction de l'activite de fond pour un dosage, a l'aide de glycoproteines comportant des glucides oxydes Download PDF

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Publication number
WO1997016727A1
WO1997016727A1 PCT/US1996/016885 US9616885W WO9716727A1 WO 1997016727 A1 WO1997016727 A1 WO 1997016727A1 US 9616885 W US9616885 W US 9616885W WO 9716727 A1 WO9716727 A1 WO 9716727A1
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Prior art keywords
glycoprotein
oxidized
bti
antibody
modified
Prior art date
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PCT/US1996/016885
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English (en)
Inventor
Michel G. Awwad
Sonny Abraham
Mary E. White-Scharf
James A. Hope
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Biotransplant, Inc.
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Publication date
Application filed by Biotransplant, Inc. filed Critical Biotransplant, Inc.
Priority to AU74645/96A priority Critical patent/AU7464596A/en
Publication of WO1997016727A1 publication Critical patent/WO1997016727A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2806—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD2
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/962—Prevention or removal of interfering materials or reactants or other treatment to enhance results, e.g. determining or preventing nonspecific binding

Definitions

  • Glycoproteins particularly monoclonal antibodies of rat or mouse origin, are increasingly being used for the treatment and diagnosis of cancer, infections, and immunological diseases.
  • an immune response is sometimes generated by patients against these antibodies.
  • the response is defined by the difference between the reactivity of the pre- and that of the post-treatment serum or plasma with the infused antibody.
  • a pre ⁇ treatment serum reactivity with the therapeutic protein is typically detected.
  • This reactivity can be attributed to the presence in human serum or plasma of "natural antibodies" reactive with the antibody and in particular with the carbohydrate portion of the administered glycoprotein. Since the pretreatment serum reactivity with the glycoprotein might either conceal or augment the real immune response, reduction of this reactivity is desired.
  • oxidized glycoprotein- associated carbohydrates results in a much lower pretreatment reaction with "natural antibodies” as compared to the unmodified forms, i.e., reduces the background level of reactivity of human serum to these glycoproteins so that it is less likely to interfere with and accurate determination of pre- and post-treatment patient reactivities.
  • Modification can be achieved chemically, enzymatically or by the use of glycosylation inhibitors in tissue cultures producing the glycoprotein, e.g., monoclonal antibody.
  • aglycosylated "glycoproteins” can be produced using molecular biology techniques .
  • the invention provides a method for determining the levels of immune responsiveness to a glycoprotein in an individual being treated therewith which comprises contacting a body fluid sample obtained from said individual prior to glycoprotein treatment with the glycoprotein that has been modified to have an oxidized carbohydrate portion; contacting a body fluid sample obtained from said individual after glycoprotein treatment with the glycoprotein that has been modified to have an oxidized carbohydrate portion; and observing the degree of difference in the specific binding response of the oxidized glycoprotein with the pre- and post-treatment samples.
  • the oxidized carbohydrate portion of the modified glycoprotein is oxidized by the presence of aldehyde groups on the carbohydrate portion. It is particularly preferred that the oxidized carbohydrate portion of the modified glycoprotein has at least about three aldehyde groups .
  • the glycoprotein for which levels of responsiveness are being determined is an antibody, particularly a xenogeneic antibody or a monoclonal antibody.
  • the level of responsiveness is measured by an in vi tro assay of serum from said individual.
  • the invention provides a composition for determining the levels of specific immune responsiveness to a glycoprotein in pre- and post- treatment samples in an individual being treated therewith which comprises: the glycoprotein that has been modified to have an oxidized carbohydrate portion; and means for observing the degree of difference in the specific immune response of the oxidized glycoprotein with the pre- and post- treatment samples.
  • the composition is an in vi tro assay composition and the oxidized carbohydrate portion of the modified glycoprotein is oxidized by the presence of aldehyde groups on the carbohydrate portion. It is particularly preferred that the oxidized carbohydrate portion of the modified glycoprotein has at least about three aldehyde groups.
  • the glycoprotein for which levels of responsiveness are being determined is an antibody, particularly a xenogeneic antibody or a monoclonal antibody.
  • Conditions for the chemical as well as the enzymatic modification process vary with the level and type of glycosylation of a glycoprotein.
  • Figure 1 shows reactivity of different sera from healthy blood donors with rat monoclonal antibody BTI-322. Positive control is hyper-immune serum obtained from chimpanzee immunized with BTI-322 (chimp) . Concentration of serum used was 0.4%.
  • Figures 2A-2D show the A 280 HPLC profiles of two batches of oxidized BTI-322 ( Figures 2A and 2B) , and that of the unoxidized BTI-322 Reference Standard ( Figure 2C) and molecular weight markers ( Figure 2D) .
  • the HPLC profile of Reference Standard BTI-322 shows that 95% of the preparation consisted of monomer.
  • oxidized BTI-322 elution profiles showed a second peak which constituted about 13% or 27% of the sample, respectively. Probably, this peak consists of aggregated BTI-322. Based on the retention time, this fraction consists mainly of BTI-322 dimers.
  • Figures 3A and 3B show that aggregates detected by HPLC were also detected by SDS-PAGE under non-reducing ( Figure 3B) as well as reducing ( Figure 3A) conditions.
  • Oxidized BTI- 322 with the exception of an additional aggregate band, has a similar migration pattern and the same number of bands as the Reference Standard.
  • Specific binding assays are based on the specific interaction between a bindable analyte under determination and a binding partner therefor, i.e. analyte-specific moiety.
  • the former situation is normally referred to as heterogeneous and the latter as homogeneous, in that the latter does not require a separation step.
  • the assay is known as an immunoassay.
  • compositions include a label conjugate comprising a binding component incorporated with a label.
  • the binding component in the conjugate participates with other constituents, if any, of the reagent composition and the ligand in the medium under assay to form a binding reaction system producing two species or forms of the conjugate, e.g., a bound-species (conjugate complex) and a free-species.
  • a bound-species conjugate complex
  • the binding component of the conjugate is bound by a corresponding binding partner whereas in the free species, the binding component is not so bound.
  • the amount or proportion of the conjugate that results in the bound species compared to the free species is a function of the presence (or amount) of the analyte to be detected in the test sample.
  • An alternative format for specific binding assays is the "sandwich" assay protocol in which the target analyte is bound between a first specific binding partner, which is fixed directly or through a linkage group to a solid matrix, and a second specific binding partner, which is associated with a signal generating or labeling system.
  • Additional immunoassay formats and protocols are also known in the art and are applicable to use in the present invention.
  • Various binding assays using immobilized or immobilizable materials for the direct immobilization of one of the binding participants in a binding assay reaction, e.g. , immobilized antigen or antibody, in order to accomplish the desired separation of the bound and free forms of a labeled reagent, have been proposed.
  • a number of such binding assays have been described wherein an antibody to an antigen to be detected is bound to an immobilizing material such as the inner wall of a test tube or a plastic bead.
  • a competitive binding assay is disclosed wherein a reaction is carried out in a test tube having a specific antibody to a hapten under determination insolubilized or immobilized on the inner wall of the test tube.
  • the reaction includes a labeled hapten conjugate wherein the quantity of the labeled hapten conjugate which becomes bound to the test tube wall is inversely proportional to the amount of the hapten under determination.
  • U.S. Pat. No. 4,298,685 discloses an enzyme immunoassay wherein a sample containing a biological substance under determination is mixed with antibodies to the biological substance tagged with biotin and with an enzyme-labeled form of the substance under assay. An immobilized form of avidin is then added wherein the avidin binds to the biotin-tagged antibody to immobilize the antibody-bound fraction of the enzyme-labeled reagent.
  • United Kingdom Patent Application No. GB 2, 084, 317A discloses an antigen-linked competitive enzyme immunoassay using avidin bound to a solid material and a biotin-labeled antigen. Radiolabeled and enzyme-tagged immunoassays require some type of separation step.
  • U.S. Pat. No. 3,817,837 discloses a competitive binding assay method involving the steps of combining the liquid to be assayed with a soluble complex consisting of an enzyme as a labeling substance covalently bound to the ligand to be detected and with a soluble receptor, usually an antibody, for the ligand; and analyzing for the effect of the liquid to be assayed on the enzymatic activity of the enzyme in the complex.
  • the labeled reagent can include other conventional detectable chemical group.
  • detectable chemical group can be any material having a detectable physical or chemical property. Such materials have been well-developed in the field of immunoassays and in general any label useful in such methods can be applied to the present invention.
  • Particularly useful are enzymatically active groups, such as enzymes (see Clin. Chem. (1976)22:1243), enzyme substrates (see U.S. Pat. No. 4,492,751) , prosthetic groups or coenzymes (see U.S. Pat. Nos. 4,230,797 and 4,238,565) , and enzyme inhibitors (see U.S. Pat. No. 4,134,792) ; spin labels; fluorescers (see Clin. Chem.
  • BTI-322 a rat anti-human CD2 antibody, currently is being used in clinical studies.
  • hypo-immune animals relates to chimpanzees that were injected and then boosted, 9 months later, with BTI-322.
  • pre-immune serum refers to serum harvested from animals (Chimpanzees) before infusion of BTI-322.
  • pre-dose serum refers to serum from patients before infusion of BTI-322 or from healthy blood donors.
  • Antibodies The following antibodies were used in conjunction with the ELISA assay: BTI-322 rat monoclonal anti-human CD2 (BioTransplant, Inc.) ; unmodified and HRP- conjugated rabbit immunoglobulin to rat immunoglobulin (Dako) ; HRP-conjugated donkey anti-human IgG antibody (Accurate) ; mouse anti-rat IgG 2b antibody (Imex, MARG2b-3) ; and a cocktail of HRP-conjugated mouse anti-rat K chain antibodies (Imex, MARK-1/3-PO) .
  • Oxidation was achieved by sodium m- periodate (Sigma) .
  • the efficiency of oxidation was determined by para-nitrophenyl hydrazine (pNPH, ICN) reaction (1) .
  • O-phenylenediamine Dihydrochloride (OPD, Sigma) at a concentration of 0.091 mg/mL in phosphate citrate buffer with urea hydrogen peroxide (Sigma) was used as an ELISA color development reagent.
  • Tween 20 (Sigma) in PBS (Sigma) was used as an ELISA washing buffer and 1% BSA (Sigma) in PBS- Tween was used to block ELISA plates.
  • Tris buffer (Sigma) was used for storage of oxidized antibody.
  • HARA Assay Briefly, 96-well plates (certified Maxisorb Nunc-Immuno plates) were coated with 50 ⁇ L of 5 ⁇ g/mL of unmodified or oxidized BET-322. A decreasing concentration of pre- and hyper-immune chimp sera as well as human serum was loaded onto the coated plates. Bound chimp and human gamma-globulins were detected by donkey anti-human IgG. Color development was then achieved by OPD.
  • Oxidation BTI-322 (Lot No. S082/S3) , at a concentration of . 5 mg/mL, was incubated at 770-fold molar ratio with sodium m-periodate . The oxidized antibody was then desalted on a prepacked PD-10 gel filtration column
  • Molarity was calculated using 208000 and 8100 as the values for the molar extinction coefficients of BTI-322 and pNPH, respectively.
  • a molecule of unmodified (native) and oxidized BTI-322 typically contained less than 1 and ⁇ 3 aldehydes groups, respectively.
  • ELISA electrospray sorbent assay
  • Oxidized BTI-322 The biochemical stability of oxidized antibody was compared to that of the unmodified BTI-322 by comparing the HPLC (size exclusion) elution profiles and SDS-PAGE migration patterns of these antibody forms were compared. Briefly, 50 ⁇ L of oxidized and unoxidized BTI-322 were loaded onto Water HPLC (Millipore) and eluted with PBS. The A 2B0 HPLC elution profiles of the different forms of BTI-322 were compared.
  • the migration patterns on SDS-PAGE were produced by loading about 5 ⁇ g of oxidized or unoxidized BTI-322 under reducing and non-reducing conditions onto 4-20% gels
  • BTI-322 The immunoreactivity of BTI-322, i . e . , its reactivity with CD2, was assessed using plates coated with recombinant soluble human CD2 (50 ⁇ L/well of 5 ⁇ g/mL) . These plates were loaded with a graded dose of oxidized and unoxidized BTI-322. Captured antibodies were then detected by rabbit immunoglobulin to rat immunoglobulin conjugated to HRP (DAKO) . Color development was achieved using the substrate o-phenylenediamine dihydrochloride (OPD) . Reactivity of the two forms of BTI-322 to rabbit polyclonal antibody was determined in an assay similar to that of immunoreactivity except that the capture antibody was unconjugated rabbit immunoglobulins to rat immunoglobulins.
  • OPD substrate o-phenylenediamine dihydrochloride
  • Reactivity with mouse monoclonal antibodies was determined by using mouse anti-rat IgG2b (MARG2b-3, IMEX) to capture the two forms of BTI-322 and HRP-conjugated mouse monoclonal antibodies to rat K chain to detect captured antibodies. Color development was achieved, as usual, using OPD.
  • Chimpanzee serum was collected from 2 animals 14 days after being boosted with BTI-322, approximately 9 months after the priming dose. Day 14 sera were pooled and used as positive control in every experiment on every plate. Chimpanzee serum was diluted at first 50-fold, starting concentration, followed by 7 five ⁇ fold dilutions. Dilution was achieved in PBS-Tween (0.5%) . Human serum was collected from healthy blood donors that were naive to rat immunoglobulin. In other words, these donors had no documented previous exposure to rat immunologlobulin. The reactivity of human serum with BTI-322 was assessed using HARA assay (see above) .
  • ELISA data were analyzed by comparing averages of triplicates of optical density readings .
  • HPLC data were analyzed by comparing the A 280 elution profile of unmodified BTI-322 to that of the oxidized form. This involved comparing the proportions of monomer in the different preparations.
  • SDS-PAGE data were analyzed by comparing the number of bands and the migration pattern of the different BTI-322 forms under reduced and non-reduced conditions.
  • Reactivity of Human and Chimpanzee Serum with BTI-322 Reactivity of Pre- and Hyper-Immune Chimpanzee Serum with BTI-322. Antibodies generated against BTI-322 following infusion into patients must be monitored and quantified. Since patients' sera were not available, pooled hyperimmune sera from 2 chimps that were injected with BTI-322 and then boosted about 9 months later were used as positive control. Table 1 shows the reactivity in a HARA assay of pre- and hyper-immune chimpanzee sera with BTI-322. Optical density readings obtained using hyper-serum were significantly higher than those obtained using pre-immune chimp serum. This indicates that hyper-immune serum contains anti-BTI-322 antibodies.
  • Oxidation of BTI-322 At least three different batches of oxidized antibody were produced by incubation of BTI-322, in complete darkness, with sodium m-periodate for 1 hour. Oxidized antibody was then desalted on prepacked G-23m Sephadex columns. After two rounds of oxidation, the molar ration of pNPH to oxidized BTI-322 was 3, 4 and 10 as compared to 0.6 of un-oxidized control BTI-322. These results indicate that whereas no free aldehyde groups could be found in un-oxidized BTI-322, 3-10 groups could be found in oxidized antibody. These results indicate that oxidation was successful .
  • Figures 2A-2D shows the size exclusion profiles (A 2B0 ) of two batches of oxidized BTI-322 ( Figures 2A and 2B) and that of the Reference Standard.
  • HPLC profile of Reference Standard Figure 2C shows that >95% of the same consisted of monomer.
  • oxidized BTI-322 elution profiles showed a second peak which constituted about 13% or 27%, respectively of the two preparations. Probably, this peak consists mainly of BTI-322 aggregate. Based on the retention time, this aggregate consists mainly of BTI-322 dimers.
  • Figure 2A shows the A 2B0 Waters HPLC profile of a first batch of oxidized BTI-322, where the reported test sample analysis was as follows:
  • Figure 2B shows the A 2 ⁇ 0 Waters HPLC profile of a second batch of oxidized BTI-322, where the reported test sample analysis was as follows: Analysis of Test Sample
  • Figure 2C shows the A 280 Waters HPLC profile of an unoxidized BTI-322, where the reported test sample analysis was as follows :
  • Figure 4D shows the A 280 Waters HPLC profile of molecular weight standards, where the reported test sample analysis was as follows: Analysis of Test Sample
  • Figures 3A and 3B show the SDS-PAGE migration pattern of oxidized [Lanes 8, 7, 6 and 5] , unoxidized [Lanes 3 and 4 (Reference Standard)] , sample buffer (Lane 2) , and molecular weight standards (Lane 1) under reducing ( Figure 3A) and no- reducing ( Figure 3B) conditions. Under non-reduced as well as reduced conditions, oxidized BTI-322 has an identical migration pattern and the same number of bands as the Reference Standard.
  • results in Table 6 demonstrate that oxidation of BTI-322 can cause 5-20 fold reduction in the reactivity of BTI-322 with serum from an individual (H23) that is naive to rat gamma-globulin.
  • Table 6 Reactivity of Chimpanzee serum with oxidized BTI-322

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Abstract

L'invention concerne une composition et une méthode permettant d'évaluer la réponse immunitaire spécifique d'une glycoprotéine chez un individu traité par ladite composition. Pour cela: (i) on met en contact un échantillon de liquide corporel prélevé chez l'individu avant le traitement par la glycoprotéine modifiée de façon à comporter une partie glucidique oxydée; (ii) on met en contact un échantillon de fluide corporel prélevé chez l'individu après un traitement par la glycoprotéine modifiée de façon à comporter une partie glucidique oxydée; et (iii) on observe la différence entre les échantillons avant et après traitement en ce qui concerne la réponse immunitaire spécifique de la glycoprotéine oxydée.
PCT/US1996/016885 1995-11-01 1996-10-18 Reduction de l'activite de fond pour un dosage, a l'aide de glycoproteines comportant des glucides oxydes WO1997016727A1 (fr)

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Application Number Priority Date Filing Date Title
AU74645/96A AU7464596A (en) 1995-11-01 1996-10-18 Assay background reduction using glycoproteins with oxidized carbohydrates

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US08/548,340 1995-11-01
US08/548,340 US5856106A (en) 1995-11-01 1995-11-01 Determination of antibody production against administered therapeutic glycoproteins, especially monoclonal antibodies

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Cited By (6)

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WO2007024949A3 (fr) * 2005-08-25 2007-06-07 Schering Corp Agonistes d'alpha 2c adrenorecepteur
WO2008137885A1 (fr) * 2007-05-07 2008-11-13 Wyeth Elimination d'interférences provoquées par des anticorps antiglucides dans le cadre de dosages immunologiques
US7560538B2 (en) 2003-11-05 2009-07-14 University Of Pittsburgh Porcine isogloboside 3 synthase protein, cDNA, genomic organization, and regulatory region
US7700592B2 (en) 2005-08-25 2010-04-20 Schering Corporation α2C adrenoreceptor agonists
US7795493B2 (en) 2002-08-21 2010-09-14 Revivicor, Inc. Porcine animals lacking any expression of functional alpha 1, 3 galactosyltransferase
US8106251B2 (en) 2002-08-21 2012-01-31 Revivicor, Inc. Tissue products derived from porcine animals lacking any expression of functional alpha 1,3 galactosyltransferase

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CA2257357C (fr) * 1996-06-07 2010-04-13 Neorx Corporation Anticorps humanises a glycosylation modifiee
US20030124091A1 (en) * 2001-10-26 2003-07-03 Large Scale Biology Corporation Endothelial cell derived hematopoietic growth factor

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7795493B2 (en) 2002-08-21 2010-09-14 Revivicor, Inc. Porcine animals lacking any expression of functional alpha 1, 3 galactosyltransferase
US8106251B2 (en) 2002-08-21 2012-01-31 Revivicor, Inc. Tissue products derived from porcine animals lacking any expression of functional alpha 1,3 galactosyltransferase
US10130737B2 (en) 2002-08-21 2018-11-20 Revivicor, Inc. Tissue products derived from animals lacking any expression of functional alpha 1, 3 galactosyltransferase
US10912863B2 (en) 2002-08-21 2021-02-09 Revivicor, Inc. Tissue products derived from animals lacking any expression of functional alpha 1, 3 galactosyltransferase
US11172658B2 (en) 2002-08-21 2021-11-16 Revivicor, Inc. Porcine animals lacking expression of functional alpha 1, 3 galactosyltransferase
US7560538B2 (en) 2003-11-05 2009-07-14 University Of Pittsburgh Porcine isogloboside 3 synthase protein, cDNA, genomic organization, and regulatory region
WO2007024949A3 (fr) * 2005-08-25 2007-06-07 Schering Corp Agonistes d'alpha 2c adrenorecepteur
US7700592B2 (en) 2005-08-25 2010-04-20 Schering Corporation α2C adrenoreceptor agonists
US7985748B2 (en) 2005-08-25 2011-07-26 Pharmacopeia Drug Discovery, Inc. ALPHA2C adrenoreceptor agonists
WO2008137885A1 (fr) * 2007-05-07 2008-11-13 Wyeth Elimination d'interférences provoquées par des anticorps antiglucides dans le cadre de dosages immunologiques

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US5856106A (en) 1999-01-05

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